Dexmedetomidine Based Sedation for Post-surgery Critically Ill Adults: A Meta-analysis of Randomized Controlled Trials.

Background
Using dexmedetomidine (Dex) as a sedative agent may benefit the clinical outcomes of post-surgery patients. We reviewed randomized controlled trials (RCTs) to assess whether use of a Dex could improve the outcomes in post-surgery critically ill adults.


Methods
We searched Medline, Embase, PubMed, and the Cochrane databases for RCTs comparing Dex with propofol or a placebo in post-operative patients, all included RCTs should be published in English before Jul 2016. Citations meeting inclusion criteria were full screened, and trial available data were abstracted independently and the Cochrane risk of bias tool was used for quality assessment.


Results
Sixteen RCTs involving 2568 patients were subject to this meta-analysis. The use of a Dex sedative regimen was associated with a reduce delirium prevalence [odd ratio (OR):0.33, 95% confidence intervals (CI): 0.24-0.45, I2= 5%, P<0.001], a shorter the length of ICU stay [mean difference (MD): -0.60, 95%CI: -0.69 to -0.50, I2=40%, P<0.001] and the length of hospital stay [MD: -0.68, 95%CI: -1.21 to -0.16, I2=0%, P=0.01]. However, using of Dex could not shorter the duration of mechanical ventilation [MD: -10.18. 95%CI: -31.08-10.72, I2=99%, P=0.34], but could shorter the time to extubation in post-surgery patients [MD: -47.46, 95%CI: -84.63-10.67, I2=98%, P=0.01].


Conclusion
The use of a Dex sedative regimen was associated with a reduce delirium prevalence, a shorter the length of ICU and hospital stay, and a shorter time to extubation in post-surgery critical ill patients.


Introduction
Approximately 30% of patients suffer delirium, anxiety, and stress after surgery (1). To maintain safety and improve comfort, an optimal sedation regimen is essential for treatment of post-surgery patients in intensive care unit (ICU). A most appropriate sedative drug which long-term used in ICUs should be quick in onset and offset, cheaper, without additional adverse effects, and can be able to facilitate daily ICU procedure, reduce anxiety, improve tolerance of mechanical ventilation, shorten the length of ICU and/or hospital stay, and reduce the morbidity and mortality (2,3). So far, there is no sedative medicine possess full of these ideal properties.
Nowadays, propofol is a preferred sedative widely used in anesthesia and ICU, which offers many advantages over benzodiazepines, such as rapid onset, easy adjustment, lack of accumulation, and quick recovery (4). Propofol has both effects of sedative and hypnotic, which mediate GABA receptor but no analgesic effect (5). Adverse reaction from propofol included respiratory depression, hypotension, hypertriglyceridemia, unpredictable duration of action, and propofol infusion syndrome (6). Moreover, propofol and benzodiazepines have also been found that might be related to the high risk of delirium (7). Dexmedetomidine (Dex) is a relatively new agent increasingly used in anesthesia and ICU in the past decade. Dex blunts the central nervous system excitation by stimulating α-2-adrenergic receptor in the locus coeruleus (8). Compare with other sedative drugs, Dex also has other potential analgesic effects, which can reduce the incidence of delirium, shorten mechanical ventilation duration, lower hospital cost, and induce a sedation and analgesia condition close to physiologic sleep but no respiratory depression. Although Dex has so many ideal properties for sedation in ICUs, its benefits and risks impact on outcomes of post-surgery critically ill patient, remain uncertain. In particular, some new large randomized controlled trials (RCTs) have not yet to be included in any meta-analysis. Thus, this updated meta-analysis will compare Dex with propofol or placebo in terms of the delirium prevalence, duration of mechanical ventilation, time to extubation, the length of ICU stay and adverse reaction in post-surgery critically ill adults.

Trial Identification
Two researchers independently conducted a literature search of Medline, Embase, PubMed, and the Cochrane databases; all included papers should be randomized controlled trials (RCTs) and published in English before Jul 2016. We only searched the studies provide the results from adults (age >18 yr old). Case reports, review, the letters, and comments were excluded from the primary search. Search keywords were ''dexmedetomidine (Dex)'' with ''sedation'', 'sedative agent'', ''analgesia'', ''critically ill'', post-operative (including post-operative, post-operation, and surgery). Only RCTs comparing Dex with propofol or a placebo were included. The trials that used Dex as anesthesia in the process of operation but continue to apply in the ICU for sedation less than 6h were excluded. Additional studies were identified according to "Google Scholar" by screening the reference lists of the related papers.

Data Abstraction
Two investigators browsed all included studies to determine whether they fulfilled all criteria of inclu-sion and recorded the features and outcomes of trial by a data abstraction form independently. The primary outcome of this study was the delirium prevalence, with secondary outcomes including time to extubation, duration of mechanical ventilation, the length of ICU stay and adverse reaction. All publication RCTs were retrieved and extracted the data. Any disagreement with opinions was resolved by means of consensus with all investigators.

Risk of Bias Assessment
Two reviewers independently conducted methodological quality assessment. The Cochrane risk of bias tool was used to evaluate the quality of included trials (9). The following seven different domains constituted the methods adequacy of sequence generation; allocation concealment; blinding of outcome assessment; blinding of participants and caregivers; incomplete outcome data and other bias. A judgment of high, low or unclear risk of material bias was made for each item according to the methods. Statistical Analysis Continuous outcomes (such as duration of mechanical ventilation and time to extubation) were calculated as mean difference (MD) with 95% confidence intervals (CI) using a random-effects model. Categorical outcomes (such as the delirium prevalence, hypotension, tachycardia, and bradycardia) were calculated as odds ratio (OR) with 95% CIs using a fixed-effects model. The heterogeneity among RCTs was evaluated using the Chi-square statistics, and the inconsistency degree was evaluated by the I 2 statistic. Significant heterogeneity existed among the RCTs when I 2 >50%. Publication bias was evaluated by the funnel plot. The data were analyzed using Review Manager (ver. 5.2, the Cochrane Collaboration, UK, 2003), and a P-value<0.05 was considered as significant difference in this meta-analysis.

Trial Characteristics
The features of all included RCTs presented in Table 1, including patient number and population, Dex loading dose, Dex sustain infusion dose, experimental and control interventions, sedation levels, and outcomes used in the metaanalysis. Eleven studies enrolled post-surgery patients from two or more center, and five studies from single center (14,18,19,21,23). The age of included patients was older on average (64±23 yr old) and critically ill (average APACHE II score=23). The largest study contained 700 post-surgery patients (25), whereas the smallest study included 28 post-surgery patients (14,19). Ten trials studied critically ill patients after cardiac and vascular surgery (10, 13, 15-17, 19, 20, 22-24), and five trials studied non-cardiac surgery (12,14,18,21,25), and one trial studied the patient after cardiac and non-cardiac surgery. Eight trials compared Dex with placebo, and eight studies compared Dex with propofol. A loading dose of Dex was used in twelve studies. The maximum maintenance doses of Dex ranged 0.2 to 0.7μg/kg/h. With except one study routinely monitored sedation (14), all trials included an established goal.

Discussion
In this meta-analysis, sixteen RCTs met the inclusion criteria and used to assess the effects of Dex on the outcomes of post-surgery critical ill adults.
The results suggested that the use of Dex in postsurgery patients was associated with reducing delirium prevalence, 0.60 d shorter length of ICU stays, 0.68 d shorter length of hospital stay, 47.46 h shorter time to extubation. The use of Dex was associated with increased risk of hypotension and bradycardia, but reduced risk of tachycardia. The potential favorable pharmacologic characteristics of Dex could help to decrease the risk of delirium in critically ill patients, but the results of these studies remained controversial (26,27). In our study, we involved seven RCTs and found a decreased risk of delirium after using Dex for post-surgery critically ill patients. Dex sedation was associated with reduced morbidity of delirium in critically ill patients with post-cardiac surgery (28,29). Contrarily, using Dex in ICU pa-tients had not decrease the risk of delirium in their results of meta-analysis (30).
The different results of meta-analyses for risk of delirium might be included following reasons. Firstly, some included RCTs needed to adjust sedative agents to reach the targeted sedation level. However, many studies reported different risk of delirium and by different assessment scales of sedation. Secondly, most included studies titrated the dose of Dex on the basis of required sedation level, but no one study used mandatory daily sedation interruption to avoid over-sedation. Thirdly, some included RCTs excluded critically ill patients with neurological diseases and cannot communicate. Dex was very effective in decrease the length of ICU stay, therefore, Dex might be more functional for critically ill patients as a supplementary therapy (31). Our results also indicated that use of a Dex was able to reduce significantly the length of ICU stay in post-surgery critical ill patients. Dex did provide more advantages than traditional sedative agents. As well as results of published meta-analyses previously confirmed the using of Dex could reduce the length of ICU stay (32), but for post-surgery critically ill patients this was the first meta-analysis to our knowledge.  The increased risk of bradycardia with Dex was well agreed with the results of a meta-analysis based on post-cardiac critically ill patients (33). However, our meta-analysis also showed that use of Dex could decrease risk of tachycardia (Fig.  10). The increased risk of bradycardia was lead to increased risk of hypotension (Fig. 8), as thus need interventions, such as decreasing the Dex infusion rate, fluid resuscitation, using vasopressors (34). New and large RCTs included might be able to explain the reason of different findings between two meta-analyses. This meta-analysis has several limitations. Firstly, our included RCTs involved post-cardiac surgery and post non-cardiac critically ill patients, and some included RCTs were small sample and single center. Therefore, these factors might lead to a relative overestimation of results in small trials. Secondly, for Dex interventions, variation greatly of the dose and duration among studies might generate different effects. Thirdly, the study shows that sedation protocols significantly affects long-term prognosis of critically ill patients (35). Fourthly, our meta-analysis just included the English language paper, so publication bias may exist. However, no study was designed to show a statistical difference in ICU and/or hospital mortality, and there was no pooled RCT reported about long-term prognosis about critically ill patients, so Dex effected long-term prognosis remain uncertain.

Conclusion
The use of a Dex sedative regimen was associated with a reduce delirium prevalence, a shorter the length of ICU and hospital stay, and the use of Dex was association with a shorter of time to extubation in post-surgery critical ill patients. Moreover, Dex treatment might increase the risk of hypotension and bradycardia but decreased the risk of tachycardia. More large RCTs are needed to further clarify which kinds of post-surgery critically ill patients can gain maximum benefit from using Dex as a primary sedative agent.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.